Large-scale population analysis confirms reassuring safety profile of tirzepatide

As more people with type 2 diabetes (T2D) are taking medications to help manage blood sugar levels and weight loss, concerns about whether these drugs are safe have emerged. Now real-world evidence from the FDA Adverse Event Reporting System (FAERS) database reveals a reassuring safety profile for tirzepatide (TZP).

The findings to be presented at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD), Madrid (9-13 Sept.), and published in the The Journal of Endocrinological Investigation reveal that compared to the widely used class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), TZP has similar gastrointestinal (GI) tolerability, without increased risk of pancreatitis, diabetic retinopathy (vision loss in T2D caused by damage to the blood vessels in the retina) and medullary thyroid cancer.

“Tirzepatide has shown unprecedented glucose and body weight lowering efficacy in individuals with type 2 diabetes and/or obesity. Now, our real-world study confirms its reassuring safety profile compared to other GLP-1 RAs such as semaglutide,” said lead author Dr. Irene Caruso from the University of Bari Aldo Moro in Italy.

GLP-1 RAs, a group of drugs used to treat T2D, are increasingly used to manage obesity by reducing appetite and slowing gastric emptying.

TZP, a newer dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), has shown even greater weight loss, crucial for reducing the risk of T2D and improving health outcomes in those with obesity or T2D.

Randomized controlled trials have shown the safety profile of TZP to be similar to that of GLP-1RAs, and mainly characterized by adverse GI events.

However, concerns about TZP’s potential link to diabetic retinopathy, pancreato-biliary disorders (diseases affecting the pancreas, gallbladder, and bile ducts), and medullary thyroid cancer have arisen, but evidence is still lacking and inconclusive.

To find out more, researchers mined the FAERS post-marketing surveillance database—that includes reports from manufacturers, patients, and health professionals—to find out whether the same safety concerns emerged from real world experiences.

Researchers retrieved reports of adverse events for TZP related to GI disorders, pancreatitis, cholecystitis (gallbladder inflammation) and cholelithiasis (gallstones), diabetic retinopathy, and thyroid neoplasms. A reporting odds ratio (ROR) was calculated to assess the disproportionality of reporting of certain adverse events associated with TZP in comparison to any other drug.

The analysis was then filtered for reports concerning age, gender, and the designated primary suspect drug. Adverse event occurrence with TZP was also compared to other diabetes treatments, including insulin, SGLT-2 inhibitors, metformin, and GLP-1RAs (both individually and as a class).

Out of the 20,409 reports referring to 1,432 adverse events, the researchers analyzed 7,460 reports, referring to 286 selected adverse events (GI, pancreato-biliary, eye-related and thyroid cancer), of which 22 showed a disproportionate signal.

Disproportionate reporting of several adverse GI events was detected with TZP. Specifically, reports of eructation (burping) were 30 times more likely with TZP compared to other drugs, while nausea, dyspepsia (indigestion), constipation, and pancreatitis were four times more likely to be reported with TZP compared to all other drugs.

However, TZP was associated with a similar risk of GI adverse events as other GLP-1RAs, with some differences including a lower risk of nausea and a greater risk of constipation. As expected, TZP exhibited a greater risk of most GI adverse events compared to insulin and SGLT-2 inhibitors.

No disproportionate reporting of pancreatitis with TZP was found compared to SGLT-2 inhibitors, but a greater risk was described compared to insulin and a lower risk reported versus GLP-1RAs.

Researchers also identified disproportionate reporting of medullary thyroid cancer with TZP, with 13 times greater odds compared to all other drugs (based on three events). However, TZP was associated with a similar risk of medullary thyroid cancer as other GLP-1RAs and SGLT-2 inhibitors, and a greater risk compared to insulin.

Similarly, reports of diabetic retinopathy (based on 12 diabetic retinopathy events) were over three times more likely with TZP compared to all other drugs. But TZP showed a similar risk to SGLT-2 inhibitors and a consistently lower risk compared with GLP-1RAs and insulin.

No disproportionate reporting of gallbladder and biliary-related adverse events was found, except for an increased risk of biliary colic compared to all other drugs and insulin. A similar risk of biliary colic was reported in comparison to GLP-1RAs and SGLT-2i.

The identified associations were confirmed when restricting the analysis to the designated primary suspect drug, TZP.

“An increasing number of people are living with type 2 diabetes and obesity, and understanding which medications can effectively manage these conditions and prevent severe side effects is crucial for their health and quality of life,” said Dr. Caruso.

She added, “Our finding suggests that tirzepatide could potentially have a similar if not improved safety profile compared to GLP-1RAs. However, the study is limited by its observational nature, the relatively short experience with tirzepatide in everyday clinical use, non-randomized comparisons, potential data incompleteness and duplication, demanding a cautious approach to its interpretation.”